3-(sulfamoylmethyl)-1,2-benzisoxazole, also named 1,2-benzisoxazole-3-methanesulfonamide and known as zonisamide is an active pharmaceutically agent that exhibits anti-convulsive and anti-neurotoxic activity and is therefore used as an anti-epileptic agent. Zonisamide has the following chemical formula:

A process of preparing zonisamide was first described in U.S. Pat. No. 4,172,896, to Uno H. et. al. (Dainippon Pharmaceutical Co.). The process taught in this patent is illustrated in Scheme 1 below and is effected by brominating benzioxazole acetic acid (also referred to herein as BIOA) to thereby provide 3-bromomethyl-1,2-benzisoxazole (Compound I); reacting 3-bromomethyl-1,2-benzisoxazole with sodium sulfite in a methanol-water mixture at 50° C., so as to obtain sodium 1,2-benzisoxazole-3-methanesulfonate (Compound II), which is also referred to hereinafter as BIOS-Na; reacting the thus obtained BIOS-Na with a large excess of phosphorus oxychloride so as to obtain 1,2-benzisoxazole-3-methanesulfonyl chloride (Compound III), which is also referred to hereinafter as BIOS-Cl); and reacting the thus obtained BIOS-Cl with gaseous ammonia in ethyl acetate to thereby obtain the zonisamide. The zonisamide is then recrystallized from ethyl acetate.

As is demonstrated in the Examples section that follows, while practicing the process taught in U.S. Pat. No. 4,172,896, it was found that the crude intermediate BIOS-Na is obtained by this process as a monohydrate (see, Reference Example 1). While such a hydrated intermediate reacts with the chlorinated agent (e.g., phosphorous oxychloride), the presence of water leads to the formation of hydrogen chloride. Furthermore, since the chlorinating agent reacts with the water, a large access thereof should be used in order to compensate for the loss of reagent that reacts with water. Since both hydrogen chloride and phosphorous oxychloride are considered hazardous, their presence in the reaction waste poses severe environmental problems.
In order to circumvent these limitations, the BIOS-Na monohydrate intermediate must be dried before the chlorination reaction. However, drying BIOS-Na monohydrate in an oven requires a prolonged time period of about 48 hours, whereby the resulting dried BIOS-Na is hygroscopic and thus is difficult to handle and store.
Another process of preparing zonisamide also involves the preparation of BIOS-Na. In this process, BIOS-Na is formed by sulfonating BIOA, with chlorosulfonic acid, to thereby obtain benzioxazole sulfonic acid (also referred to herein as BIOS-H), which is then transformed to BIOS-Na using NaOH. However, such a sulfonation reaction is non-selective and results in a substantial amount of the disulfonated benzioxazole derivative.
WO 03/020708 (by Teva Pharmaceutical Industries Ltd.) teaches various intermediates of zonisamide, processes for their preparation and zonisamide prepared therefrom. Particularly, this patent application teaches the preparation of the sulfonic acid intermediate derivative, BIOS-H, by reacting BIOA with acetic anhydride and sulfuric acid. The BIOS-H is thereafter converted to BIOS-Na. According to the teachings of WO 03/020708, using such a process avoids the formation of the dislufonated product and further avoids the use of chlorosulfonic acid, thus being more environmentally friendly. The preparation of BIOS-Na from BIOA via BIOS-H using the process taught in WO 03/030708 is illustrated in Scheme 2 below.

Further according to the teachings of this patent, the preparation of various metallic salts (e.g., sodium, calcium and barium) of BIOS-H is described. These salts are mostly obtained in a hydrated crystalline form thereof, containing between about 1.5 and about 7 weight percentages of water. As is discussed hereinabove, the presence of water in the zonisamide intermediate obtained prior to chlorination, is highly disadvantageous since it requires the use of excess chlorinated agent and involves the production of hydrogen chloride.
WO 03/072552 (to Teva Pharmaceuticals USA, Inc.) describes a process of preparing zonisamide via the intermediate BIOS-Cl. According to the teachings of this patent application, BIOS-Cl is prepared by chlorinating 1,2-benzisoxazole-3-methanesulfonic acid (BIOS-H) or BIOS-Na with thionyl chloride (SOCl2) in an organic solvent. The BIOS-Cl is then reacted with ammonia to thereby obtain zonisamide.
The synthesis of zonisamide from BIOS-H or BIOS-Na via BIOS-Cl, as taught in WO 03/072552 is illustrated in Scheme 3 below.

Thus, the processes taught in the art for preparing BIOS-Na as an intermediate in the synthesis of zonisamide and related compound are limited by the formation of hydrated forms thereof, which either complicates the process as the presence of water requires using a molar excess of the chlorinating agents and involves formation of hydrochloric acid or requires a laborious drying process, whereby the obtained dry intermediate is highly hygroscopic.
In addition, in all of the presently known processes of preparing zonisamide, chlorinating agents such as phosphorus oxychloride, thionyl chloride and phosphorus pentachloride, being some of the most readily available chlorinating agents around the world, are utilized. These chlorinating agents are considered hazardous and in some countries, shipping into and/or ground transportation thereof is restricted. An alternative process of preparing zonisamide, which circumvents the need to use such environmentally unfriendly reagents has not been suggested nor practiced hitherto.
There is thus a widely recognized need for and it would be highly advantageous to have a novel process of preparing zonisamide and particularly a novel process of preparing intermediates thereof, devoid of the above limitations.